HIV-1 infection of women is a relatively rare outcome of sexual exposure to HIV-1. The risk may vary for each woman, and it may also vary for the same woman during different exposures. Susceptibility is determined by a complex set of factors, including the amount and properties of the virus to which a woman is exposed, individual host genetic factors, as well as multiple modifiable biological cofactors present at the time of exposure. In this program project grant, we proposed to examine the mechanisms by which biological cofactors increase susceptibility of women to HIV-1. The proposed studies will include women in multiple high-risk groups: sex workers, pregnant/postpartum women and women in HIV-1 discordant relationships. Specifically, we will examine the role of: 1) pregnancy and the postpartum effects (Project 1); 2) vaginal flora and specific bacterial infections (Project 2); 3) innate immune factors, including as they relate to hormones and genital tract infections (Project 3); and 4) mucosal HIV-1 antibodies induced in response to repeated HIV-1 exposure (Project 4) on susceptibility to HIV-1 infection in women. For these studies, we will take advantage of cohort studies, collaborative partnerships and infrastructure developed by our research team, the Seattle/Kenya collaborative research group, over the past ~ 15 years. Our research group, which includes virologists, immunologists, bacteriologists, epidemiologist, statisticians and clinical scientists, has a long and productive history of collaboration, and is known for its focus on translational research in women. Here we will build on that foundation to conduct multiple collaborative projects within this program grant. We expect that each of these projects will draw on the expertise of others in the team, and in some cases, will include parallel studies that address synergistic biological questions in the same populations.